Cancer is characterized by uncontrolled cell proliferation. Antimitotic agents and antimicrotubule agents have been explored for cancer therapy because of their important effect in the cell division. Inhibition of the mitotic machinery results in a diverse array of outcomes, primarily leading to cell cycle arrest and cell death. Antimicrotubule agents, such as taxanes are currently being used in clinical setting. For example, paclitaxel and docetaxel have a similar spectrum of clinical activity including ovarian, lung, breast, bladder, and prostate cancers. Taxanes are anti-mitotic agents that bind to tubulin and inhibit microtubule depolymerization thereby disrupting the normal equilibrium involved in microtubule assembly and deconstruction and therefore impair microtubule functioning. Microtubules are essential to cell division and cells exposed to taxanes can fail to divide. Cell cycle arrest after treatment with taxanes may eventually result in cell death due to unsuccessful mitosis. Despite the advances in anticancer therapy, there exists a long-felt need for more effective therapies with limited toxicities. Indeed, the toxicities associated with paclitaxel and docetaxel include neutropenia as the major dose limiting toxicity, along with significant peripheral neuropathy. In fact, dose reductions are frequent in heavily pretreated patients to mitigate the severity of these toxicities. On top of that, the development of resistance to taxanes also limits its use in the clinic.
Apoptosis is a highly regulated cell death pathway that is initiated by various cytotoxic stimuli, including oncogenic stress and chemotherapeutic agents. It has been shown that evasion of apoptosis is a hallmark of cancer and that efficacy of many chemotherapeutic agents is dependent upon the activation of the intrinsic mitochondrial pathway. Three distinct subgroups of the BCL-2 family proteins control the intrinsic apoptosis pathway: (i) the pro-apoptotic BH3 (the Bcl-2 homology 3)-only proteins; (ii) the pro-survival members such as BCL-2 itself, BCL-xL, BCL-W, MCL-1 and BCL-2A1; and (iii) the pro-apoptotic effector proteins BAX and BAK (Czabotar et al., Nature Reviews Molecular Cell Biology 2014, 15, 49-63). Overexpression of the anti-apoptotic members of BCL-2 family is observed in many cancers, (Adams and Cory, Oncogene 2007, 26, 1324-1337) and the pharmacological inhibition of the anti-apoptotic proteins by BH3-mimetics drugs such as ABT-199 (venetoclax), ABT-263 (navitoclax) and 563845 has emerged as a therapeutic strategy to induce apoptosis and cause tumor regression in cancer (Zhang et al., Drug Resist. Updat. 2007, 10, 207-217; Kotschy et al., Nature 2016, 538, 477-482). Nevertheless, mechanisms of resistance to BH3 mimetics have been observed (Choudhary et al., Cell Death and Disease 2015, 6, e1593) and the use of combination therapies could improve efficacy and delay or even abrogate resistance development.
Breast cancer is a heterogeneous disease and can be stratified into at least five major subgroups based on gene expression profiling: Luminal A, Luminal B (estrogen positive, ER+), HER2-amplified, basal-like (predominantly triple negative breast cancer or TNBC) and normal-like (Curtis et al., Nature 2012, 486, 346-352; Perou et al., Nature 2000, 406, 747-752). These subtypes generally predict clinical behavior with respect to response and resistance to therapy, patterns of metastasis, and overall survival. Multiple mechanisms contribute to tumor progression and resistance to cancer therapy, including the evasion of cell death due to deregulation of the balance between anti- and pro-apoptotic members of the BCL2 family (Merino et al., Oncogene 2016, 35, 1877-1887; Beroukim et al., Nature 2010, 463, 899-905; Wertz et al., Nature 2011, 471, 110-114; Goodwin et al., Cell Death Differ. 2015). In the triple-negative breast cancer subgroup, residual disease after neo-adjuvant therapy is associated with higher risk of metastatic recurrence compared to patients achieving a pathological complete response (Liedtke et al., J. Clin. Oncol. 2008, 26(8), 1275-1281). About 70% of TNBC patients do not achieve complete response after neo-adjuvant chemotherapy (such as paclitaxel or docetaxel) and suffer a dramatically worse outcome, with a higher probability of metastatic relapse and a 3-year overall survival of only 60-70%.
Lung cancer is classified into non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and carcinoid. Approximately 80% of all lung cancers correspond to NSCLC, which can be further classified into adenocarcinoma, squamous cell carcinoma, and large cell carcinoma. Lung cancer is the most common cause of cancer-related death in men and second most common in women after breast cancer. Although lung cancer therapy has evolved significantly with the appearance of targeted therapy, there is still a strong need to develop novel therapies in order to improve treatment efficacy, reduce side effects and avoid appearance of resistance (Rothschild Cancers 2015, 7(2), 930-949).
The present invention provides a novel combination of a MCL-1 inhibitor and a taxane compound. The results show that with the association of potent small molecules targeting MCL-1 with antimicrotubule agents is highly synergistic in breast and lung cancer cell lines (FIGS. 1 to 7; Tables 1 and 4). We also show that combined disrupting microtubule function and MCL-1 targeting in vivo is efficacious at tolerated doses in breast cancer PDX (Patient Derived Xenograft) models (FIGS. 8 and 9) and at different doses in female nude rats bearing MDA-MB-231 xenograft, a model of triple negative breast cancer (FIGS. 10 to 14). The positive combination was also observed on different PDX models of TNBC using different schedules of administration (FIG. 15). The synergistic effect of targeting MCL-1 and disrupting microtubule function in vitro and in vivo at tolerated doses have been demonstrated through combination of potent small molecule inhibitors. Finally, residual tumor analysis after neo-adjuvant treatment is a major and under-explored field to study chemoresistance and, thus, we perform experiments in PDX models resistant to chemotherapy showing that the combination of a MCL-1 inhibitor and a taxane compound is efficient (Example 9).